在疟疾传播强度历史上存在差异的乌干达人群中，KIR 基因及其 HLA-C 配体的多样性。
Diversity of KIR genes and their HLA-C ligands in Ugandan populations with historically varied malaria transmission intensity.
机构信息
Department of Obstetrics and Gynaecology, School of Medicine, Makerere University College of Health Sciences, P.O BOX 7072, Kampala, Uganda.
Infectious Diseases Research Collaboration, 2C Nakasero Hill Road, Kampala, Uganda.
出版信息
Malar J. 2021 Feb 25;20(1):111. doi: 10.1186/s12936-021-03652-y.
BACKGROUND
Malaria is one of the most serious infectious diseases in the world. The malaria burden is greatly affected by human immunity, and immune responses vary between populations. Genetic diversity in KIR and HLA-C genes, which are important in immunity to infectious diseases, is likely to play a role in this heterogeneity. Several studies have shown that KIR and HLA-C genes influence the immune response to viral infections, but few studies have examined the role of KIR and HLA-C in malaria infection, and these have used low-resolution genotyping. The aim of this study was to determine whether genetic variation in KIR and their HLA-C ligands differ in Ugandan populations with historically varied malaria transmission intensity using more comprehensive genotyping approaches.
METHODS
High throughput multiplex quantitative real-time PCR method was used to genotype KIR genetic variants and copy number variation and a high-throughput real-time PCR method was developed to genotype HLA-C1 and C2 allotypes for 1344 participants, aged 6 months to 10 years, enrolled from Ugandan populations with historically high (Tororo District), medium (Jinja District) and low (Kanungu District) malaria transmission intensity.
RESULTS
The prevalence of KIR3DS1, KIR2DL5, KIR2DS5, and KIR2DS1 genes was significantly lower in populations from Kanungu compared to Tororo (7.6 vs 13.2%: p = 0.006, 57.2 vs 66.4%: p = 0.005, 33.2 vs 46.6%: p < 0.001, and 19.7 vs 26.7%: p = 0.014, respectively) or Jinja (7.6 vs 18.1%: p < 0.001, 57.2 vs 63.8%: p = 0.048, 33.2 vs 43.5%: p = 0.002, and 19.7 vs 30.4%: p < 0.001, respectively). The prevalence of homozygous HLA-C2 was significantly higher in populations from Kanungu (31.6%) compared to Jinja (21.4%), p = 0.043, with no significant difference between Kanungu and Tororo (26.7%), p = 0.296.
CONCLUSIONS
The KIR3DS1, KIR2DL5, KIR2DS5 and KIR2DS1 genes may partly explain differences in transmission intensity of malaria since these genes have been positively selected for in places with historically high malaria transmission intensity. The high-throughput, multiplex, real-time HLA-C genotyping PCR method developed will be useful in disease-association studies involving large cohorts.
背景
疟疾是世界上最严重的传染病之一。疟疾负担受人类免疫的影响很大，而人群之间的免疫反应存在差异。在免疫传染病方面发挥重要作用的杀伤细胞免疫球蛋白样受体（KIR）和人类白细胞抗原-C（HLA-C）基因的遗传多样性可能在这种异质性中发挥作用。一些研究表明，KIR 和 HLA-C 基因影响对病毒感染的免疫反应，但很少有研究探讨 KIR 和 HLA-C 在疟疾感染中的作用，并且这些研究使用的是低分辨率基因分型。本研究的目的是使用更全面的基因分型方法，确定在疟疾传播强度历史上存在差异的乌干达人群中，KIR 和其 HLA-C 配体的遗传变异是否存在差异。
方法
使用高通量多重实时定量 PCR 方法对 1344 名年龄在 6 个月至 10 岁的乌干达人群的 KIR 遗传变异和拷贝数变异进行基因分型，这些人群来自疟疾传播强度历史上较高（托罗罗区）、中等（金贾区）和较低（坎昆区）的地区。使用高通量实时 PCR 方法对 HLA-C1 和 C2 同种型进行基因分型。
结果
与托罗罗相比，来自坎昆的人群中 KIR3DS1、KIR2DL5、KIR2DS5 和 KIR2DS1 基因的流行率显著降低（7.6%比 13.2%：p=0.006，57.2%比 66.4%：p=0.005，33.2%比 46.6%：p<0.001，19.7%比 26.7%：p=0.014），与金贾相比也显著降低（7.6%比 18.1%：p<0.001，57.2%比 63.8%：p=0.048，33.2%比 43.5%：p=0.002，19.7%比 30.4%：p<0.001）。来自坎昆的人群中纯合 HLA-C2 的流行率明显高于金贾（31.6%比 21.4%：p=0.043），但与托罗罗相比无显著差异（26.7%：p=0.296）。
结论
KIR3DS1、KIR2DL5、KIR2DS5 和 KIR2DS1 基因可能部分解释了疟疾传播强度的差异，因为这些基因在疟疾传播强度历史上较高的地方受到了积极选择。开发的高通量、多重、实时 HLA-C 基因分型 PCR 方法将在涉及大型队列的疾病关联研究中发挥重要作用。
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